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www.eymj.org To the Editor, Mitochondrial Encephalopathy, Lactic Acidosis, and Strokelike episodes (MELAS) syndrome is one of the most frequent syndromic mitochondrial disorders (MIDs). It is diagnosed according to the Japanese criteria if at least two features of category A [headache with vomiting, seizures, hemiplegia, cortical blindness, stroke-like lesion (SLL)] and at least two features of category B (elevated lactate in serum or cerebro-spinal fluid, mitochondrial myopathy on muscle biopsy, MELAS-related mutation) being present. MELAS is diagnosed according to the Hirano criteria if all three of the canonical features [strokelike episode (SLE) before age of 40 years, encephalopathy (seizures or dementia), and mitochondrial myopathy on biopsy] and at least two of the other features (normal early psychomotor development, recurrent headache, or recurrent vomiting) are present. Eighty percent of the MELAS cases are due to the variant m.3243A>G in MT-TL1. Other mutated genes associated with MELAS include MT-ND5, MT-TC, MT-TF, MT-TH, MT-TK, MTTL2, MT-TQ, MT-TV, MT-TW, MT-TS1, MT-TS2, MT-ND1, MTND6, MT-CO2, MT-CO3, and MT-CYB. The most frequent phenotypic manifestations of MELAS include seizures (76% of patients), headache (50% of patients), SLEs (>90%), visual loss (52% of patients), muscle weakness (48% of patients), vomiting (55%), as well as short stature (>25% of cases), impaired consciousness, impaired cognition, hearing loss, or diabetes (10– 24% of patients). Although the phenotypic spectrum of MELAS is broader than anticipated (Table 1), most of these features are rare and often reported only in a single patient or family. This is why it is sometimes questionable if these rare features are truly attributable to the MID or due to a secondary problem. Rare phenotypic manifestations occurring in <10% of the MELAS cases include cerebral manifestations (dystonia, chorea, parkinsonism), psychiatric abnormalities (delirium, confusion, mutism, hallucinations, delusions, dysexecutive syndrome), ophthalmologic manifestations (cataract, retinal detachment, maculopathy, polymegathism), otologic disease (vestibular dysfunction), endocrine abnormalities (hypoaldosteronism, Addison’s disease, hyperthyroidism, hypopituitarism, osteoporosis), cardiac manifestations (noncompaction, arterial hypertension), lungs (pulmonary hypertension, chronic obstructive pulmonary disease), gastrointestinal compromise (pancreatitis, odynophagia), kidneys (Fanconi syndrome), and vascular involvement (artery dissection, aneurysm formation, aortic rupture). Rare non-specific manifestations include developmental delay or fever (<10% of cases). Non-specific manifestations of MELAS may also include dysmorphism (hypertelorism, protruding ears). Knowing the entire spectrum of the phenotype is crucial, as prospective investigations may also be carried out for these rare features and some of them may strongly determine the prognosis and outcome. Although SLLs, the morphological equivalent of SLEs on MRI, develop predominantly in the cortex and subcortical white matter, they can rarely occur ubiquitously in the central nervous system, including the cerebellum, brainstem, the spinal cord, or the optic nerve. Though epilepsy is frequent in MELAS, certain seizures have only been infrequently reported. These include non-convulsive status epilepticus, epilepsia partialis continua, occipital status epilepticus, and myoclonic seizures. Overall, although MELAS is a frequent phenotype, we still do require more comprehensive evaluations of the phenotype to assess which features are truly attributable to a MELAS mutation to encompass the entire phenotypic spectrum of the disease. Rare phenotypic features should be regarded as part of the phenotype only if the diagnostic criteria for MELAS are met, if a MELAS-associated mutation is present, and if there is no other plausible explanation for a particular feature. It is important to describe the pathophysiological relationship between a rare phenotypic feature and the underlying mitochondrial Received: August 19, 2020 Revised: September 1, 2020 Accepted: September 3, 2020 Corresponding author: Josef Finsterer, MD, PhD, Klinik Landstrasse, Messerli Institute, Postfach 20, 1180 Vienna, Austria. Tel: 43-1-71165-72085, Fax: 43-1-71165, E-mail: [email protected]